This project will be a major focus of the lab moving forward. We have initiated several subprojects with respect to this project; the aims and accomplishments in these subprojects are listed below: A project to identify synergistic drug combinations in RAS mutated neuroblastoma was funded by NCATS, which identified a novel combination of a MEK inhibitor and a cereblon modulator. Work has begun to validate the synergy and establish a mechanism (collaboration with Carol Thiele and Craig Thomas) A project to evaluate a combination of romidepsin and the dual BRD4/PI3K inhibitor, SF2523, in RAS-driven pediatric cancers was funded by CAPR and work has begun on this project. The first aim of the project, evaluating PK after different modes of administration of romidepsin, has been completed (collaboration with Rob Robey). Evaluating the efficacy of the combination of a MEK inhibitor and pan-RAF inhibitor in RMS (collaboration with Angelina Vaseva). Evaluating the efficacy of the combination of a MEK inhibitor and a BCL-XL inhibitor in RMS (collaboration with Ben Braun). Evaluating the combination of a MEK inhibitor and a SHP2 inhibitor in NB (collaboration with Meredith Irwin). I will serve as vice-chair of the APEC1621M arm of the CTEP-COG Pediatric MATCH trial, which will evaluate the efficacy of tipifarnib in HRAS-mutant pediatric cancers (protocol in development). In addition, I am collaborating with Christine Pratilas to evaluate tipifarnib in HRAS mutated RMS preclinically. We have begun to evaluate the efficacy of KRAS G12C inhibitors in neuroblastoma (ARS-1620, AMG 510, AZD1569, MRTX849). MCRADA in place to evaluate KRAS antisense oligonucleotide in pediatric cancers (AZD4785, now Ionis).